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Author Manuscript Faculty of Biology and Medicine Publication Serveur Académique Lausannois SERVAL serval.unil.ch Author Manuscript Faculty of Biology and Medicine Publication This paper has been peer-reviewed but dos not include the final publisher proof-corrections or journal pagination. Published in final edited form as: Title: B-cell receptor-driven MALT1 activity regulates MYC signaling in mantle cell lymphoma. Authors: Dai B, Grau M, Juilland M, Klener P, Höring E, Molinsky J, Schimmack G, Aukema SM, Hoster E, Vogt N, Staiger AM, Erdmann T, Xu W, Erdmann K, Dzyuba N, Madle H, Berdel WE, Trneny M, Dreyling M, Jöhrens K, Lenz P, Rosenwald A, Siebert R, Tzankov A, Klapper W, Anagnostopoulos I, Krappmann D, Ott G, Thome M, Lenz G Journal: Blood Year: 2017 Jan 19 Volume: 129 Issue: 3 Pages: 333-346 DOI: 10.1182/blood-2016-05-718775 In the absence of a copyright statement, users should assume that standard copyright protection applies, unless the article contains an explicit statement to the contrary. In case of doubt, contact the journal publisher to verify the copyright status of an article. 1 B-cell receptor driven MALT1 activity regulates MYC signaling in mantle cell lymphoma Beiying Dai,1-3 Michael Grau,1,2 Mélanie Juilland,4 Pavel Klener,5,6 Elisabeth Höring,7 Jan Molinsky,5,6 Gisela Schimmack,8 Sietse M. Aukema,9 Eva Hoster,10,11 Niklas Vogt,1,12 Annette M. Staiger,13 Tabea Erdmann,1,2 Wendan Xu,1,2 Kristian Erdmann,1,2 Nicole Dzyuba,1,2 Hannelore Madle,1,2 Wolfgang E. Berdel,2,14 Marek Trneny,6 Martin Dreyling,10 Korinna Jöhrens,15 Peter Lenz,16 Andreas Rosenwald,17 Reiner Siebert,9,18 Alexandar Tzankov,19 Wolfram Klapper,12 Ioannis Anagnostopoulos,15 Daniel Krappmann,8 German Ott,13 Margot Thome,4 Georg Lenz1,2,14 1Translational Oncology, Albert-Schweitzer-Campus 1, University Hospital Münster, 48149 Münster, Germany; 2Cluster of Excellence EXC 1003, Cells in Motion, 48149 Münster, Germany; 3Fachbereich Chemie und Pharmazie, University of Münster, 48149 Münster, Germany; 4Department of Biochemistry, University of Lausanne, CH-1066 Epalinges, Switzerland; 5Institute of Pathological Physiology, First Faculty of Medicine, Charles University Prague, Prague, Czech Republic; 6Department of Hematology, Charles University General Hospital Prague, Prague, Czech Republic; 7 Department of Hematology and Oncology, Robert-Bosch-Hospital and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, and University of Tuebingen, Germany; 8Research Unit Cellular Signal Integration, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München - German Research Center for Environmental Health, 85764 Neuherberg, Germany; 9Institute of Human Genetics, Christian-Albrechts-University Kiel, 24105 Kiel, Germany; 10Department of Internal Medicine III, Ludwig-Maximilians-University Hospital Munich, Munich, Germany; 11Institute of Medical Informatics, Biometry, and Epidemiology, Ludwig-Maximilians- University of Munich, Munich, Germany; 12Department of Pathology, Hematopathology Section and Lymph Node Registry, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; 13Department of Clinical Pathology, Robert-Bosch-Hospital and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, and University of Tuebingen, Germany; 14Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, 48149 Münster, Germany; 15Institute of Pathology, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; 16Department of Physics, Philipps-University, 35032 Marburg, Germany; 17Department of Pathology, University of Würzburg, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany; 18Institute of Human Genetics, University Hospital Ulm, 89081 Ulm, Germany; and 19Institute of Pathology, University Hospital, Schoenbeinstrasse 40, 4031 Basel, Switzerland Short title: MALT1 and MYC signaling in MCL Scientific category: LYMPHOID NEOPLASIA Word count manuscript: 3990 Abstract word count: 183 Number of figures: 7 Number of references: 44 Corresponding author: Georg Lenz, M.D. University Hospital Münster, Translational Oncology Albert-Schweitzer-Campus 1 48149 Münster, Germany Phone: +49 251 83 52995 Fax: +49 251 83 52673 Email: [email protected] Copyright © 2016 American Society of Hematology 2 Key points • MALT1 protease activity stabilizes MYC • The MALT1-MYC network might represent a therapeutic target for MCL patients Abstract Mantle cell lymphoma (MCL) is a mature B-cell lymphoma characterized by poor clinical outcome. Recent studies revealed the importance of B-cell receptor (BCR) signaling in maintaining MCL survival. However, it remains unclear which role MALT1, an essential component of the CARD11-BCL10-MALT1 (CBM) complex that links BCR signaling to the nuclear factor kappa-B (NF-κB) pathway, plays in the biology of MCL. Here we show that a subset of MCLs is addicted to MALT1, as its inhibition by either RNA or pharmacologic interference induced cytotoxicity both in vitro and in vivo. Gene expression profiling following MALT1 inhibition demonstrated that MALT1 controls a MYC-driven gene expression network predominantly through increasing MYC protein stability. Thus, our analyses identify a previously unappreciated regulatory mechanism of MYC expression. Investigating primary mouse splenocytes, we could demonstrate that MALT1-induced MYC regulation is not restricted to MCL, but represents a common mechanism. MYC itself is pivotal for MCL survival as its downregulation and pharmacologic inhibition induced cytotoxicity in all MCL models. Collectively, these results provide a strong mechanistic rationale to investigate the therapeutic efficacy of targeting the MALT1-MYC axis in MCL patients. 3 Introduction Mantle cell lymphoma (MCL) is characterized by an aggressive clinical course and short overall survival.1 Different cytomorphological variants can be distinguished and especially, blastic variants are associated with poor overall survival.2-4 Besides clinical factors summarized in the mantle cell lymphoma international prognostic index (MIPI), high cell proliferation has been identified as a major prognostic factor associated with adverse outcome.5-7 Pathogenetically MCL is characterized by cyclin D1 overexpression due to the chromosomal translocation t(11;14)(q13;q32).8 In addition, various secondary genetic aberrations activating different pathways have been elucidated.9,10 Recently, constitutive activation of B-cell receptor (BCR) signaling and downstream activation of the nuclear factor kappa-B (NF-κB) pathway have been identified to be critical for survival of MCL subsets.11,12 Upon BCR stimulation MALT1 and BCL10 are recruited to CARD11 resulting in the formation of the CARD11-BCL10-MALT1 (CBM) complex and NF-κB activation.13,14 Additionally, the protease activity of MALT1 is enhanced leading to cleavage of NF-κB inhibitors such as A20 and RelB.15,16 Other known MALT1 substrates include BCL10, CYLD, Regnase-1, Roquin-1, Roquin-2, and HOIL1.17-25 Preliminary data suggested that MALT1 is constitutively activated in subsets of MCL.11 However, its precise role in the pathogenesis of MCL remains unknown. Thus, we investigated the role of MALT1 in the biology of MCL in the current study. 4 Methods Patient samples, immunohistochemistry and fluorescence in situ hybridization (FISH) CD20+ MCL cells were separated from peripheral blood mononuclear cells (PBMCs; patient samples #1 and #2) or cell suspensions from lymph nodes (patient samples #3-5) of MCL patients by CD20 magnetic-activated cell sorting (Miltenyi Biotec, Bergisch Gladbach, Germany). The immunohistochemical protocols are summarized in the Supplemental Material and Methods. FISH was performed as described.26,27 Cell culture, retroviral constructs and transductions The experiments were performed as described.28-30 Protocols are available in the Supplemental Material and Methods. The sequences of the utilized small hairpin RNAs (shRNAs) are summarized in Supplemental Table 1. Viability assay, analysis of cell cycle, apoptosis and proliferation The experiments were performed as described.29,31,32 Protocols are available in the Supplemental Material and Methods. Isolation and stimulation of mouse splenocytes Protocols are available in the Supplemental Material and Methods. In vivo xenograft mouse studies The in vivo xenograft mouse studies were done as described.33 Protocols are available in the Supplemental Material and Methods. 5 Gene expression profiling Gene expression profiling was performed 24, 30, 36, 42, 48, and 54 hours following treatment with z-VRPR-fmk or DMSO in Mino and Rec-1 cells and analyzed as described in Supplemental Material and Methods.32,34,35 The gene expression data has been deposited in the GEO database (http://www.ncbi.nlm.nih.gov/geo; accession number GSE81552). Quantitative PCR Quantitative PCR was performed as described using predesigned assays (Applied Biosystems, Carlsbad, CA, USA).29 Western blotting and analysis of MYC stability Protocols are available in the Supplemental Material and Methods. Results MALT1 is expressed and activated in MCL To assess if MALT1 is expressed in MCL, we determined its expression in 60 primary samples by immunohistochemistry. To establish the immunohistochemical assay, we stained five reactive lymph node and tonsil specimens. MALT1 was expressed in both B- and T-cell areas of the lymph node, albeit to varying degrees. The germinal center (GC) B-cells were strongly positive and staining was accentuated in the dark zone of the GC (Supplemental Figure 1). 56/60 (93%) of
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